Efficacy of different pretreatments in IVF outcomes in patients with endometriosis: A systematic review and network meta‑analysis

ARTICLE IN PRESS Article in Press Efficacy of different pretreatments in IVF outcomes in patients with endometriosis: A systematic review and network meta‑analysis Scientific Reports Received: 20 November 2025 Accepted: 8 May 2026 Cite this article as: Li D., Zheng L., Zhang X. et al. Efficacy of different pretreatments in IVF outcomes in patients with endometriosis: A systematic review and network meta‑analysis. Sci Rep (2026). https:// doi.org/10.1038/s41598‑026‑52918‑5 Dan Li, Lianwen Zheng, Xueying Zhang, Wei Wang, Jingshun Zhang & Lulu Fu We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply. 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To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. 1Efficacy of different pretreatments in IVF 2outcomes in patients with endometriosis: a systematic review 3and network meta‑analysis 4 5Dan Li 1, Lianwen Zheng1, Xueying Zhang1, Wei Wang2, Jingshun Zhang1, Lulu Fu1* 6 7 1Reproductive Medicine Centre, Jilin Provincial KeyLaboratory of Reproductive 8Biology（The Second Hospital of Jilin University, Changchun Jilin Province, China 9 2Department of Breast Surgery Two, Jilin Provincial Cancer Hospital, Changchun 10130000, Jilin, China 11Corresponding author: Lulu Fu [email protected] 12 13 1 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 14Abstract 15Background: To investigate the efficacy of different pretreatment protocols for women 16with endometriosis undergoing IVF. 17Methods: We systematically searched the Cochrane Library, PubMed, Medline, and 18Embase from inception to April 30, 2025, to identify randomized controlled trials 19(RCTs) evaluating different pretreatment protocols in women with endometriosis 20undergoing IVF. The primary outcomes were live birth rate and clinical pregnancy rate. 21Secondary outcomes included miscarriage rate, fertilization rate, implantation rate, 22gonadotropin dose, and number of retrieved oocytes. 23Results: This network meta-analysis included 11 randomized controlled trials 24involving 1,435 women with endometriosis undergoing IVF. No clear improvement in 25clinical pregnancy rate was observed among the pretreatment protocols compared with 26the general protocol. For live birth rate, limited evidence from four RCTs suggested a 27higher rate in the general protocol than in the GnRH-a protocol (RR [95% CI], 2.12 28[1.05, 4.31]), but this finding should be interpreted cautiously because of imprecision. 29Some differences were observed in secondary or intermediate outcomes. The number 30of retrieved oocytes was significantly higher in the general protocol than in the DNG 31protocol (MD [95% CI], 0.60 [0.24, 0.97]). The GnRH-a protocol (MD [95% CI], −2.11 32[−2.94, −1.28]) and the general protocol (MD [95% CI], −2.45 [−3.50, −1.40]) were 33associated with lower gonadotropin doses than the DNG protocol. However, these 34secondary findings did not translate into clear improvements in the prespecified primary 35clinical outcomes. 2 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 36Conclusion: The results of this network meta-analysis suggest that, compared with the 37general protocol, pretreatment with GnRH-a or DNG was not associated with clear 38improvements in the primary clinical IVF outcomes, namely clinical pregnancy rate 39and live birth rate, in patients with endometriosis. However, the evidence for live birth 40rate was limited to four RCTs and imprecise; therefore, this finding should be 41interpreted cautiously. Although some differences were observed in secondary or 42intermediate outcomes, these findings did not establish the clinical superiority of 43pretreatment protocols. PROSPERO under identifier: (CRD42024606775). 44Keywords: GnRH-a, Dienogest, Endometriosis, IVF-ET, Network meta-analysis 45Introduction 46Endometriosis（EMs（, an estrogen-driven, persistent gynecological disorder, is 47identified by the existence of functional endometrial tissue located outside the uterine 48cavity 1. Previous studies have shown that a pro-inflammatory microenvironment, 49driven by hormonal and immune factors, promotes the persistence of EMs. These 50mechanisms are associated with the two primary symptoms of the disease: pain and 51infertility 2. It is predicted that approximately 40% of women suffering EMs experience 52infertility 3. The mechanisms through which EMs contributes to infertility are 53multifactorial, involving distortion of pelvic anatomy, inflammatory responses, and 54oxidative stress that impair oocyte quality and embryo implantation 4 5 6. 55In Vitro Fertilization (IVF) has become a critical strategy in the management of 56infertility associated with EMs. However, the success rates of IVF in women suffering 57from EMs are considerably lower than those in women free of the condition 7 8, posing 3 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 58a significant clinical challenge. Various pretreatment protocols have been investigated, 59including the use of GnRH-a, dienogest (DNG), and other hormonal therapies, all aimed 60at improving IVF outcomes for women diagnosed with EMs 9. However, the findings 61across studies have been inconsistent. Some studies suggest that prolonged GnRH-a 62therapy may significantly enhance clinical pregnancy rates in women with advanced- 63stage EMs 10, 11, potentially through the reduction of inflammation and endometrial 64lesions. Additionally, progestins such as DNG are thought to offer a more favorable 65side-effect profile, while still contributing to clinical improvements, including higher 66pregnancy rates and a reduction in recurrence risk 12. However, after further 67investigation, researchers such as Anna, Xueying, Ektoras, and Becker discovered that 68pretreatment with DNG or GnRH-a does not significantly impact IVF outcomes in 69patients with EMs 13 14 15 16 . Given these conflicting findings, our study intends to 70perform a comprehensive review and assess the efficiency of various pretreatment 71protocols on outcomes of IVF in women suffering from EMs, providing evidence-based 72recommendations to guide clinicians in customizing fertility treatments for these 73patients. 74Methods 75We conducted this network meta-analysis in full compliance with the PRISMA 76Extension guidelines for Systematic Reviews and Meta-Analyses. PROSPERO 77registration was obtained for the study (registration no. CRD42024606775). 78Search strategy 79PubMed, Cochrane Library, Medline, and Embase were systematically and 4 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 80exhaustively searched for relevant articles until Apr 30, 2025. English search terms 81were ‘Endometriosis’ OR ‘EMs’ OR ‘Endometrioma’ OR ‘Endometriomas’ AND 82‘GnRH’ OR ‘Gonadotropin-Releasing Hormone’ OR ‘Luliberin OR Gonadorelin’ OR 83‘Gonadoliberin’ OR ‘dienogest’ OR ‘DNG’ AND ‘Fertilization in Vitro’ OR 84‘Fertilizations in Vitro’. 85Clinical trial registries (ClinicalTrials.gov and australianclinicaltrials.gov.au) were also 86searched, and the reference lists of relevant reviews and eligible studies were manually 87screened to identify additional potentially relevant articles. According to the predefined 88eligibility criteria, only randomized controlled trials (RCTs) evaluating pretreatment 89protocols in women with endometriosis undergoing IVF were included in the final 90analysis. The study protocol was specified in advance, with prespecified procedures for 91data identification, extraction, and analysis. 92Inclusion and exclusion criteria 93The inclusion criteria were as follows: (1) studies involving women with endometriosis 94undergoing IVF or IVF/ICSI; (2) The study groups received different pre-treatment 95protocols, which primarily included: GnRH-a protocol, with 3 to 6 months of 96administration prior to IVF; DNG protocol, with at least 3 months of administration 97prior to IVF; other pre-treatment protocols. The control group followed the general 98protocol, which was defined as conventional IVF/ICSI treatment without ≥3 months 99of endometriosis-directed hormonal pretreatment before controlled ovarian 100hyperstimulation. In this comparator category, patients proceeded directly to assisted 101reproductive technology according to the standard IVF/ICSI practice used in each 5 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 102original study, typically involving standard controlled ovarian stimulation with a 103conventional long GnRH agonist protocol, followed by gonadotropin stimulation, hCG 104triggering, oocyte retrieval, and IVF/ICSI-embryo transfer; (3) studies reporting at least 105one of the outcomes as follows: re0trieved oocytes, r-FSH levels, duration of 106stimulation, rates of fertilization, implantation, miscarriage, live birth and clinical 107pregnancy; (4) randomized controlled trials (RCTs). Endometriosis was defined 108according to the diagnostic criteria reported in the original studies. Where available, 109information on surgical confirmation, histopathological findings, imaging-based 110diagnosis, clinical diagnosis, and disease stage was extracted. 111The exclusion criteria were as follows: (1) studies involving infertility mainly 112attributable to other major factors, such as severe male-factor infertility; (2) non- 113randomized studies, retrospective studies, prospective observational studies, case 114reports, reviews, conference abstracts, and duplicate publications; (3) studies with 115insufficient data for extraction or analysis. 116Data collection and quality evaluation 117 Two independent reviewers extracted data from the eligible studies, assessed study 118eligibility, and evaluated the methodological quality of the included trials. 119Disagreements were resolved through discussion or, when necessary, consultation with 120a third reviewer. Extracted data included study characteristics, intervention protocols, 121sample size, patient age, and outcome indicators. In addition, whenever reported, 122information on the diagnostic basis of endometriosis was collected, including surgical 123confirmation, histopathological findings, imaging-based diagnosis, clinical diagnosis, 6 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 124and disease stage. The Cochrane Collaboration’s tool was employed to assess bias risk 125in the RCTs 17. The bias risk was rated as low, unclear, or high. The certainty of 126evidence for key outcomes was additionally assessed using the GRADE framework. 127The assessment considered risk of bias, inconsistency, indirectness, imprecision, and 128publication bias. The certainty of evidence was rated as high, moderate, low, or very 129low. 130Clinical Outcomes 131Primary outcomes: live birth rate and clinical pregnancy rate. Secondary outcomes: (1) 132miscarriage rate; (2) fertilization rate; (3) implantation rate; (4) dose of gonadotropin; 133(5) number of oocytes collected. 134Statistical analyses 135We first used the network map command in STATA 17.0 to assess the network 136configuration of the available data, evaluating all pretreatment protocols before IVF for 137patients with EMs 18. When feasible, pooled effect estimates were computed from direct 138comparisons of each treatment pair using a random-effects REML model to account for 139expected between-study variability. Effect measures were reported as risk ratios (RRs) 140with 95% confidence intervals (CIs) for dichotomous variables and as mean differences 141(MDs) for continuous variables. Clinical and methodological heterogeneity was 142assessed qualitatively by examining reported differences in diagnostic criteria, 143endometriosis stage, prior surgical history, embryo transfer type, pretreatment duration, 144and IVF/ICSI protocols. Because these potential effect modifiers were incompletely 145and inconsistently reported across studies, formal subgroup analyses, sensitivity 146analyses, or network meta-regression could not be performed reliably. To assess 7 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 147inconsistency, the node-splitting method was applied, comparing direct and indirect 148evidence within the network. This approach incorporates both types of evidence to 149determine the relative effects and rankings 19. Surface Under the Cumulative Ranking 150Curve (SUCRA) was used to summarize the relative ranking probabilities of different 151protocols within the treatment network. SUCRA rankings were interpreted together 152with the corresponding effect estimates, 95% confidence intervals, risk of bias, and 153certainty of evidence, rather than as standalone evidence of clinical superiority. The 154comparison-adjusted funnel plot was utilized to assess publication bias. 155Results 156Study selection and Characteristics of included studies 157A total of 743 records were identified from four databases, and 11 RCTs were 158ultimately included in the quantitative analysis 12 20 21 22 23 24 25 26 27 28 29 (Figure 1). 159Overall, 1,435 patients were included, with 810 in the pretreatment protocols and 625 160in the general protocol. The characteristics of the included studies are summarized in 161Table 1. The distribution of reported potential effect modifiers across treatment nodes 162is summarized in Supplementary Table 1, including diagnostic basis of endometriosis, 163disease stage or phenotype, prior surgical history, pretreatment duration, embryo 164transfer type, IVF/ICSI protocol, and age where available. Because these variables were 165not uniformly reported across all trials, their distribution could only be assessed 166qualitatively. 8 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 167 168Quality assessment of the studies included 169Risk-of-bias assessment showed that several studies were rated as having low or unclear 170risk in domains such as random sequence generation, incomplete outcome data, and 171selective reporting. However, eight of the eleven included trials were judged to be at 172high risk of bias in the blinding of participants and personnel domain, mainly because 173blinding was difficult to implement given the nature of the interventions. In addition, 174five studies were rated as high risk in the blinding of outcome assessment domain. Only 175one study was considered to have a high risk of bias due to incomplete outcome data, 176one study due to selective reporting, and one study due to allocation concealment. 177Overall, performance bias and detection bias were the most common methodological 178concerns among the included studies (Figure 2). The high risk of bias in the blinding 9 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 179domain reduced confidence in the synthesized estimates. Lack of blinding may have 180introduced performance bias, particularly for cycle-related or management-dependent 181outcomes, such as gonadotropin dose, stimulation management, and treatment 182adherence. Although live birth rate and clinical pregnancy rate are relatively objective 183outcomes and may be less susceptible to detection bias, the overall certainty of evidence 184was downgraded for several outcomes because of risk of bias, imprecision, and clinical 185heterogeneity. The GRADE certainty assessment for the key outcomes is presented in 186Supplementary Table 2. 187 10 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 188Network Meta-Analyses 189Results of the network meta-analysis: No statistically significant inconsistency was 190detected in the inconsistency tests (P > 0.05), and the consistency model was therefore 191used for the main analyses. The node-splitting method was applied to assess local 192inconsistency, with all P-values > 0.05, suggesting no significant disagreement between 193direct and indirect evidence for the evaluated outcomes. However, the absence of 194statistical inconsistency should not be interpreted as evidence of clinical homogeneity, 195given the incomplete reporting of key patient- and treatment-level characteristics across 196the included trials. The network relationship diagram for the web meta-analysis is 197shown in Supplementary Figure 1. We evaluated four treatment regimens within the 198network: (A) DNG, (B) GnRH-a, (C) general protocol, and (D) ethinylestradiol + DNG. 199The comparison focused on rates of clinical pregnancy, live birth, miscarriage, 200fertilization, and implantation, r-FSH levels, and the count of oocytes collected. 201 202Clinical Pregnancy Rate 203The analysis of seven RCTs showed the following SUCRA ranking probabilities for 204clinical pregnancy rate: GnRH-a group, general protocol, DNG group, and 205ethinylestradiol + DNG group (Figure 3a). However, the interval plot comparing effect 206estimates showed no statistically significant differences among the four groups (Figure 2074a). Specifically, the comparisons were as follows: DNG group vs. GnRH-a protocol 208(RR [95% CI], 1.55 [0.56, 4.30]); DNG group vs. general protocol (RR [95% CI], 1.12 209[0.44, 2.88]); DNG group vs. ethinylestradiol + DNG protocol (RR [95% CI], 0.84 210[0.20, 3.58]); GnRH-a protocol vs. general protocol (RR [95% CI], 0.73 [0.35, 1.49]); 11 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 211GnRH-a protocol vs. ethinylestradiol + DNG group (RR [95% CI], 0.54 [0.11, 2.61]); 212and general protocol vs. ethinylestradiol + DNG protocol (RR [95% CI], 0.54 [0.11, 2132.61]). Therefore, these SUCRA rankings should be interpreted cautiously and should 214not be considered evidence of clinical superiority. 215Live Birth Rate 216Four RCTs reported live birth rate. The SUCRA ranking indicated the following order, 217from most to least favorable: general protocol, DNG group, and GnRH-a group (Figure 2183b). The interval plot suggested a higher live birth rate in the general protocol than in 219the GnRH-a protocol (RR [95% CI], 2.12 [1.05, 4.31]). However, no statistically 220significant differences were observed between the DNG protocol and the GnRH-a 221protocol (RR [95% CI], 0.96 [0.41, 2.28]) or between the DNG protocol and the general 222protocol (RR [95% CI], 2.05 [0.82, 5.14]) (Figure 4b). Because only four RCTs 223contributed data to this outcome and several confidence intervals were wide, these 224findings should be interpreted cautiously. 225Miscarriage Rate 226For miscarriage rate, a lower rate was considered more favorable. According to SUCRA ranking 227probabilities, the general protocol ranked most favorably, followed by the GnRH-a group and the 228DNG group (Figure 3c). However, no statistically significant differences were observed among the 229GnRH-a protocol, DNG protocol, and general protocol. Specifically, the risk ratios were as follows: 230DNG protocol vs. general protocol (RR [95% CI], 0.92 [0.23, 3.70]) and GnRH-a protocol vs. 231general protocol (RR [95% CI], 0.93 [0.38, 2.31]) (Figure 4c). Therefore, the SUCRA ranking for 232miscarriage rate should be interpreted cautiously. 233Fertilization Rate 12 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 234According to SUCRA ranking probabilities, the order for fertilization rate was GnRH- 235a group, general protocol, and DNG group (Figure 3d). The interval plot showed that 236fertilization rate was higher in the GnRH-a protocol than in the DNG protocol (RR [95% 237CI], 2.69 [1.11, 6.51]). However, no statistically significant differences were observed 238between the pretreatment groups and the general protocol. Specifically, the risk ratios 239were as follows: DNG group vs. general protocol (RR [95% CI], 2.32 [0.87, 6.17]) and 240GnRH-a group vs. general protocol (RR [95% CI], 0.86 [0.57, 1.31]) (Figure 4d). 241Therefore, although a protocol-specific difference was observed, this secondary 242outcome should not be interpreted as evidence of overall clinical superiority unless it 243translates into improved primary clinical outcomes. 244Implantation Rate 245According to SUCRA ranking probabilities, the order was DNG group, GnRH-a group, 246and general protocol (Figure 3e). No meaningful differences were found among the 247three intervention groups. DNG protocol VS GnRH-a protocol (RR [95%CI]; 0.72 248[0.28, 1.81]); DNG protocol VS General protocol (RR [95%CI]; 0.61 [0.26, 1.42]); 249GnRH-a protocol VS General protocol (RR [95%CI]; 0.85 [0.58, 1.25]) (Figure 4e). 250Dose of Gonadotropin 251For gonadotropin dose, a lower dose was considered more favorable. According to 252SUCRA ranking probabilities, the order was general protocol, GnRH-a group, and 253DNG group (Figure 3f). The interval plot showed that both the GnRH-a group (MD [95% 254CI], −2.11 [−2.94, −1.28]) and the general protocol group (MD [95% CI], −2.45 [−3.50, 255−1.40]) had significantly lower gonadotropin doses than the DNG group (Figure 4f). 256However, no statistically significant difference was observed between the GnRH-a 13 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 257group and the general protocol (MD [95% CI], −0.34 [−0.98, 0.30]) (Figure 4f). 258Because gonadotropin dose is a cycle-related outcome, this finding should be 259interpreted as reflecting differences in ovarian stimulation requirements rather than 260direct evidence of improved clinical reproductive outcomes. 261Number of Retrieved Oocytes 262According to SUCRA ranking probabilities, the order was general protocol, GnRH-a 263group, and DNG group (Figure 3g). The interval plot comparing the effect sizes for 264collected oocytes numbers revealed that the GnRH-a protocol (MD [95% CI]; 0.39 265[0.09, 0.69]) and the general protocol (MD [95% CI]; 0.60 [0.24, 0.97]) had slightly 266higher collected oocytes numbers compared to the DNG group. However, no 267meaningful difference was found between the GnRH-a protocol and the general 268protocol (MD [95% CI]; 0.21 [-0.13, 0.55]) (Figure 4g). The more information of the 269network side-split and the cumulative probability network rank test are shown in 270Supplementary Figure 2,3 271 14 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 272 273Risk of Bias Across Studies 274Publication bias was assessed using funnel plots (Figure 5), which plot individual study 275effect sizes against their standard errors. Asymmetry in the plots may suggest the 276presence of unpublished small studies with negative results. It should be noted, however, 277that funnel plot asymmetry may also arise from heterogeneity or differences in study 278quality. 15 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 279 280Discussion 281To the best of our knowledge, this is the first network meta-analysis to assess the 282efficacy and safety of different pretreatment protocols before IVF in women with 283endometriosis. Network meta-analysis allows simultaneous comparison of multiple 284interventions by integrating direct and indirect evidence across trials with different 285comparison groups 30. 286Overall, we included 11 randomized controlled trials involving 1,435 patients. The 287findings of individual studies were not fully consistent. Among studies evaluating DNG 288pretreatment, one trial suggested that pretreatment may benefit patients with stage II– 289III endometriosis by improving IVF success rates 20, whereas Tamura et al 21. reported 290that DNG pretreatment was associated with less favorable IVF outcomes. Another 291study found no significant differences between DNG and GnRH-a pretreatment in 292ovarian stimulation, response parameters, or pregnancy outcomes 12. Similarly, among 293studies evaluating GnRH-a, some trials suggested that prolonged GnRH-a pretreatment 294for 3–6 months may improve IVF outcomes in women with endometriosis-related 16 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 295infertility 20 22 25 27 29, whereas other trials did not support the effectiveness of an ultra- 296long GnRH-a protocol in improving IVF outcomes 23 24 28. 297These mixed findings highlight the importance of interpreting the results according to 298the prespecified outcome hierarchy. In this review, the main conclusions were based on 299the primary clinical outcomes, namely live birth rate and clinical pregnancy rate. 300Although some secondary or intermediate outcomes differed between protocols, these 301findings mainly reflect laboratory, ovarian response, or cycle-related parameters and 302should be regarded as supportive rather than definitive evidence of clinical benefit. 303To better understand these mixed clinical findings, it is necessary to consider the 304biological effects of GnRH-a and DNG. Undoubtedly, GnRH-a is recognized for its 305proliferation-suppressing and inflammation-reducing effects, which help modulate the 306hormonal environment in patients with Ems 31. And it could make pituitary cells 307unresponsive to endogenous GnRH-a to achieve desensitization, reduce the secretion 308of FSH and luteinizing hormone (LH), inhibit ovarian activity, reduce the level of 309estradiol, and promote atrophy of ectopic foci to favor embryo implantation 32. The 310ultra-long protocol, by extensively inhibiting ovarian function through receptor 311downregulation, reduces pituitary sensitivity, which often results in a prolonged 312duration and increased dosage of gonadotropins, leading to a poor ovarian response, 313fewer follicles, smaller follicular diameters, reduced oocyte retrieval, and a lower 314number of embryos 33. Haouzi and van claim that long-duration GnRH-a therapy during 315ovarian stimulation cycles may impair endometrial receptivity, with animal studies 316indicating that the ultra-long protocol downregulates the expression of key molecules 17 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 317such as CDH1, CTNNB1, Meis1 and Hoxa11, further affecting endometrial receptivity 318 34 35 36 37. 319Currently, the effect of pretreatment on live birth rate remains inconsistent across 320studies. In our network meta-analysis, although 11 RCTs were included overall, live 321birth rate was reported by only four RCTs. The available evidence suggested a higher 322live birth rate in the general protocol than in the GnRH-a protocol; however, because 323only four RCTs contributed data and the confidence intervals were relatively wide, this 324estimate should be interpreted cautiously. This finding contrasts with a previous review 325 38. Their meta-analysis included only three trials 22 25 29, comprising data from 165 cases 326and 78 pregnancies, and suggested that prolonged GnRH-a pretreatment might improve 327pregnancy outcomes despite no increase in the number of retrieved oocytes. The authors 328attributed this potential benefit to improved oocyte quality or enhanced endometrial 329receptivity. The Cochrane meta-analysis conducted by Georgiou et al. 15 included eight 330parallel-design RCTs involving 640 participants, but the quality of evidence was rated 331as very low to low, primarily because seven of the eight studies lacked adequate 332blinding. In turn, a recent review encompassing 16 studies, including 10 RCTs, 3 333retrospective cohorts, and 3 comparative studies, concluded that GnRH-a 334administration did not have a statistically significant effect on follicle count, total or 335mature oocyte count, embryo count, embryo quality, or miscarriage rate. Given the lack 336of updated evidence and the limitations of existing studies, including small sample sizes, 337insufficient statistical power, unequal study-group matching, and limited data on 338complications or live birth rate, the authors did not recommend GnRH-a pretreatment 18 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 339before IVF as a strategy to improve clinical pregnancy rates 39. 340Similarly, pretreatment with DNG may face comparable challenges 40. DNG exerts its 341effects through negative feedback regulation of the hypothalamic-pituitary-ovarian axis, 342alleviating dysmenorrhea, suppressing ovulation, reducing estrogen levels, and 343shrinking ovarian endometriotic cysts. Notably, the reduction in cyst size becomes 344more pronounced with longer treatment duration 41. Additionally, DNG is known to 345suppress follicular growth and promote follicular atresia, further contributing to its 346therapeutic effects in EMs management 42. One study involving 568 women with EMs 347in 5 studies (2 RCTs and 3 cohort studies) suggested that pregnancy outcomes with the 348DNG protocol were significantly better than with no hormonal treatment. Subgroup 349analysis showed higher clinical pregnancy and live birth rates in the DNG group for 350fresh embryo transfer 43. However, in our review, we found no significant trend 351favoring DNG therapy for improving clinical pregnancy or live birth rates. Our results 352align with those of a recent review, which also found that pretreatment with DNG did 353not improve live birth or clinical pregnancy rates in females with EMs undergoing IVF 354 44. The reason for this could be that DNG can lessen the recruitment of primordial 355follicles, which could further reduce the number of follicles that are growing. This is 356often clinically reflected in a higher proportion of immature oocytes and lower 357fertilization rates 45. This discrepancy may also stem from the inclusion of more recent 358randomized controlled trials in our analysis, and the exclusion of cohort studies. The 359RCTs we included used modern stimulation protocols, randomized larger sample sizes, 360and incorporated more rigorous study designs—such as placebo controls and 19 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 361comparisons between females suffering from EMs and females affected by other 362infertility etiologies—making them more methodologically robust than earlier studies. 363 These mechanisms may explain why the DNG pretreatment group did not show 364superior outcomes compared to the general protocol. Additionally, the extended 365duration of stimulation and higher gonadotropin requirements led to increased patient 366inconvenience, higher medical costs, and delayed conception, without a corresponding 367improvement in clinical outcomes. Based on these findings, the currently available 368evidence does not support a robust additional benefit of pretreatment protocols for 369improving the primary reproductive outcomes in patients with EMs undergoing IVF, 370although differences in some secondary or cycle-related outcomes may warrant further 371investigation. 372These findings are also consistent with a recent network meta-analysis evaluating 373hormone pretreatment before ART in infertile women with endometriosis, which 374likewise failed to demonstrate clear superiority of hormonal suppression over 375immediate ART for improving key reproductive outcomes 46. This external consistency 376supports a cautious interpretation of the current evidence base. Likewise, comparative 377work examining IVF/ICSI versus surgery as the initial approach for endometriosis- 378associated infertility highlights that disease-directed interventions should not 379automatically be assumed to improve reproductive outcomes simply because they are 380biologically or surgically plausible 47. More broadly, similar issues have been observed 381with endocrine or adjunctive strategies in reproductive medicine. Recent literature 382suggests that biologically plausible interventions may affect intermediate, laboratory, 20 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 383or cycle-related outcomes, yet such effects do not necessarily translate into consistent 384improvements in live birth outcomes 48 49 50. Therefore, in women with endometriosis 385undergoing IVF, mechanistic plausibility and protocol-level changes should be 386interpreted cautiously unless supported by robust evidence of benefit in patient- 387important outcomes such as live birth and clinical pregnancy. 388The interpretation of these pooled estimates should also consider the clinical and 389methodological heterogeneity of the included trials. Differences in disease stage, 390diagnostic criteria, prior surgical history, embryo transfer strategy, pretreatment 391duration, and IVF/ICSI protocols may have influenced treatment effects. Although 392statistical inconsistency was not detected, the limited number of studies and incomplete 393reporting of potential effect modifiers restricted our ability to formally explore these 394sources of heterogeneity. Therefore, the pooled estimates should be regarded as overall 395average effects across heterogeneous trial populations rather than as effects directly 396applicable to every clinical subgroup. 397The risk-of-bias assessment in our study also affected the interpretation of the pooled 398estimates. Blinding of participants and personnel was difficult to implement in most 399included IVF trials because pretreatment protocols differed in drug type, duration, and 400administration schedule. This may have introduced performance bias, particularly for 401outcomes influenced by clinical management or cycle decisions, such as gonadotropin 402dose, stimulation duration, and cycle planning. Although the primary outcomes, 403including live birth rate and clinical pregnancy rate, are relatively objective and may be 404less vulnerable to detection bias, the high risk of bias in the blinding domain still 21 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 405reduces confidence in the overall evidence. 406Limitation 407First, the number of eligible studies available for analysis was limited. In particular, 408although live birth rate was prespecified as a primary outcome, only four RCTs reported 409this endpoint. This limited evidence base resulted in imprecise estimates, as reflected 410by the wide confidence intervals in several comparisons. Therefore, conclusions 411regarding live birth rate should be considered exploratory and interpreted with caution. 412Second, important clinical details, including diagnostic criteria for endometriosis, 413disease stage, prior surgical history, embryo transfer type, pretreatment duration, and 414IVF/ICSI protocols, were incompletely and inconsistently reported across studies. 415Because individual patient-level data were unavailable and several outcome networks 416were sparse, subgroup analyses, sensitivity analyses, or covariate adjustments could not 417be performed reliably. Therefore, the generalizability of the pooled estimates may be 418limited, and the results should be interpreted as overall average effects rather than as 419effects applicable to all clinical subgroups. Third, the certainty of evidence was limited 420by methodological concerns, particularly the high risk of bias in the blinding domain. 421Although blinding is inherently challenging in IVF trials comparing different 422pretreatment regimens, this limitation may have affected treatment implementation, co- 423interventions, and cycle management, thereby reducing confidence in the synthesized 424estimates. The GRADE assessment indicated that the certainty of evidence for several 425key outcomes was low to moderate, mainly because of risk of bias, imprecision, and 426clinical heterogeneity. Future large-scale, multicenter randomized controlled trials with 22 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 427standardized and comprehensive reporting of key clinical and treatment-related factors 428are needed to improve the reliability, interpretability, and clinical applicability of the 429evidence. 430Conclusion 431To the best of our knowledge, this is the first network meta-analysis to compare the 432efficacy of different pretreatment protocols before IVF/ICSI in women with 433endometriosis. Based on the currently available evidence, pretreatment protocols were 434not associated with clear improvements in the primary clinical IVF outcomes, namely 435live birth rate and clinical pregnancy rate, compared with the general protocol. 436Although some secondary outcomes and SUCRA rankings suggested protocol-specific 437differences, these findings did not establish the clinical superiority of pretreatment 438protocols. This conclusion should be interpreted cautiously because of the limited 439number of eligible trials, clinical heterogeneity, risk of bias, and imprecision of some 440estimates, particularly for live birth rate. Pretreatment may still be considered for 441selected patient-centered indications, such as symptom control or cycle planning, but 442routine use solely to improve IVF success rates is not strongly supported by current 443evidence. Further large-scale, well-designed randomized controlled trials with 444standardized reporting of diagnostic criteria, disease stage, prior surgical history, 445embryo transfer type, and pretreatment duration are needed to confirm these findings. 446Abbreviations 447EMs Endometriosis 448IVF In Vitro Fertilization 23 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 449GnRH-a Gonadotropin-Releasing Hormone agonist 450DNG Dienogest 451RCT Randomized Controlled Trial 452CI Confidence Interval 453RR Risk Ratio 454MD Mean Difference 455SUCRA Surface Under the Cumulative Ranking Curve 456PRISMA Preferred Reporting Items for Systematic Reviews and 457Meta-Analyses 458FSH Follicle-Stimulating Hormone 459r-FSH Recombinant Follicle-Stimulating Hormone 460ET Embryo Transfer 461CPR Clinical Pregnancy Rate 462ART Assisted Reproductive Technology 463LH Luteinizing Hormone 464MII Metaphase II (oocytes) 465REML Restricted Maximum Likelihood 466ICSI Intracytoplasmic Sperm Injection 467Author Contributions 468DL performed the experiments, analyzed the data, prepared figures and table and 469approved the final draft. LWZ conceived and designed the experiments, authored and 470reviewed drafts of the article, and approved the final draft. XYZ conceived and 24 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 471designed the experiments, authored and reviewed drafts of the article, and approved the 472final draft. WW conceived and designed the experiments, authored and reviewed drafts 473of the article, and approved the final draft. JSZ conceived and designed the experiments, 474authored and reviewed drafts of the article, and approved the final draft. LLF conceived 475and designed the experiments, authored and reviewed drafts of the article, and approved 476the final draft. 477Funding 478The author(s) declare financial support was received for the research, authorship, 479and/or publication of this article. This research was supported by the Natural Science 480Foundation of Jilin Province (YDZJ202301ZYTS434) 481Data availability statement 482No datasets were generated or analysed during the current study. 483Declarations 484 Consent for publication 485 Not applicable. 486Competing interests 487 The authors declare no competing interests. 488Ethical approval and consent to participate 489 This study was a meta-analysis of previously published data. Therefore, no 490additional ethical approval or patient consent was required. 491 Clinical trial number 492 Not applicable. 493 494Reference 4951. Vercellini, P., Viganò, P., Somigliana, E. & Fedele, L. Endometriosis: 496pathogenesis and treatment. Nature reviews. Endocrinology 10, 261-275 25 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS 497(2014). 4982. Gupta, S. et al. Pathogenic mechanisms in endometriosis-associated 499infertility. Fertility and Sterility 90, 247-257 (2008). 5003. Leone Roberti Maggiore, U. et al. 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Adjuvant treatment strategies in ovarian stimulation for poor 648responders undergoing IVF: a systematic review and network meta-analysis. 649Hum Reprod Update 26, 247-263 (2020). 29 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS Table 1 The basic characteristics of the included studies Author Year Group Interventions N Age (years) Outcomes Dienogest A 3-month treatment with DNG (2 mg daily) before IVF 67 36.1±2.7Khalifa 2021 GnRH-a A 3-month treatment with GnRH-a (3.75mg monthly) before IVF 36 35.6±3.5 The number of oocytes retrieved, the number of mature oocytes, fertilization rate, Clinical pregnancy rate （Miscarriage rate（ No. of transferrable embryos（Total dose of FSH (IU) Dienogest A 3- month treatment with DNG (2 mg daily) before IVF 30 34.2±3.4Tamura 2019 General protocol Standard controlled ovarian hyperstimulation 34 33.6±3.6 The numbers of mature follicles, retrieved oocytes, and fertilized oocytes, the fertilization rates, implantation rates, and clinical pregnancy rates Dienogest A 3-month treatment with DNG (2 mg daily) before IVF 45 22-38 GnRH-a A 3-month treatment with GnRH-a (3.75mg monthly) before IVF 38 22-38 COCs and Dienogest A 3-month treatment with Ethinylestradiol (30mcg daily) and DNG (2 mg daily) before IVF 45 22-38 Aksenenko 2021 General protocol Direct IVF 70 22-38 Medication tolerance, clinical and laboratory characteristics, the state of the uterus depending on the stage of EMs (confirmed by ultrasound), and pregnancy rate GnRH-a A 6-month treatment with GnRH-a (3.75mg monthly) before IVF 28 23-40Rickes 2002 General protocol Direct IVF 19 23-40 Pregnancy rate at the end of the treatment (without considering the number of cycles) GnRH-a A 3-month treatment with GnRH-a (3.75mg monthly) before IVF 200 34.8±3.8Kaponis 2020 General protocol IVF without GnRH-a 200 32.8±2.9 Follicular fluid (FF) levels of tumor necrosis factor a (TNF-a), interleukin-1b (IL-1b), IL-6, IL-8, and IL-1 receptor antagonist; fertilization rate (FR), implantation rate (IR), quality of embryos, and clinical pregnancy rate (PR) GnRH-a A 3-month treatment with GnRH-a (3.75mg monthly) before IVF 100 33.86±3.08Elisabet 2020 General protocol Direct IVF 100 33.72±3.25 Clinical pregnancy rate (CPR) per started cycle, cumulative CPR per patient, implantation rate, miscarriage rate, cumulative live birth rate, multiple pregnancy rate; and variables related to controlled ovarian stimulation: estradiol levels, number of MII oocytes, number of embryos and embryo quality GnRH-a A 3-month treatment with GnRH-a (3.75mg monthly) before IVF 25 33.12±0.67Surrey 2002 General protocol Standard controlled ovarian hyperstimulation 26 32.58±0.56 Response to controlled ovarian hyperstimulation, ongoing pregnancy rates per cycle, group implantation rates, and implantation rate per embryo transfer procedure. GnRH-a A 3-month treatment with GnRH-a (3.75mg monthly) before IVF 61 30.3 ± 3.63Decleer 2016 General protocol Standard controlled ovarian hyperstimulation 59 31.7±4.28 Number of MII oocytes, pregnancy rate, embryo transfer, Total FSH dose (IU), days stimulation, embryo quality, pregnancy rate GnRH-a A 3-month treatment with GnRH-a (3.75mg monthly) before IVF 45 30.8±1.2Maged 2018 General protocol Standard controlled ovarian hyperstimulation 45 31.2±1.4 Chemical and clinical pregnancy rates, ongoing pregnancy, miscarriage, ectopic pregnancy, and multiple pregnancy rates GnRH-a A 3-month treatment with GnRH-a (3.75mg monthly) before IVF 21 31.4±3.9Tomassetti 2021 General protocol Standard controlled ovarian hyperstimulation 21 32.4± 3.7 Clinical pregnancy rate, cumulative delivery rate, antral follicle count on the day of start of stimulation, cumulus oocyte complex retrieved, duration of stimulation, fertilization rate, embryo quality, embryo utilization rate, implantation rate, other pregnancy outcomes (miscarriage, ectopic, delivery, live birth) 30 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS Table 1 The basic characteristics of the included studies（Continued（ Author Year Group Interventions N Age (years) Outcomes GnRH-a A 6-month treatment with GnRH-a (3.2mg monthly) before IVF 35 31 ± 5Dicker 1992 General protocol FSH combined with human menopausal gonadotrophin starting on the 3rd day of the cycle with administration of 3 ampules per day of either preparation. 32 32 ± 4 Clinical pregnancy rate, the number of oocytes, fertilization rate, cleavage rate, the number of transfers, the number of preclinical pregnancies, the number of clinical pregnancies Figure 1 Flow of studies through the review Figure 2 Risk of bias summary and graph Figure 3 SUCRA ranking probabilities of outcome indicators A, DNG group; B, GnRH- a group; C, General protocol; D, Ethinylestradiol + DNG Figure 4 Forest plot for outcome indicators. a, Clinical pregnancy rate; b, live birth rate c, miscarriage rate; d, fertilization rate; e, implantation rate; f, dose of gonadotropin; g, number of retrieved oocytes. A, DNG group; B, GnRH-a group; C, General protocol; D, Ethinylestradiol + DNG Figure 5 Publication bias funnel plot. a, Clinical pregnancy rate; b, live birth rate; c, miscarriage rate; d, fertilization rate; e, implantation rate; f, dose of gonadotropin; g, number of retrieved oocytes. A, DNG group; B, GnRH-a group; C, General protocol; D, Ethinylestradiol + DNG 31 ACCEPTED MANUSCRIPTARTICLE IN PRESS ARTICLE IN PRESSARTICLE IN PRESS